Nicastrin (NCT), a type I transmembrane glycoprotein which forms high molecular weight complexes with presenilins (PS), is an essential component of the multimeric gamma-secretase complex required for both gamma-secretase activity and APP trafficking. Our recent studies suggest that NCT, with its large ectodomain, may be a potential therapeutic target for AD. Because PS/gamma-secretase activity is required for a variety of essential signaling pathways coupled with our recent finding that cognitive deficits occur in BACE1 null mice, complete inhibition of either secretase activity may not be completely free of mechanism-based toxicity. To minimize any potential toxicity, it may be beneficial to modulate both beta- and gamma-secretase activity such that a significant amelioration of Abeta deposition occurs without affecting other critical signaling pathways. Since our recent studies showed that Abeta deposits are sensitive to the dosage of both NCT and BACE1, we hypothesize that Abeta deposits could be ameliorated by decreasing levels of NCT and BACE1. As proof of principal, we will examine in Aim 1 whether partial reductions of NCT or both NCT and BACE1 will reduce Abeta burden in brains of mutant APP;PS1 mice. Based on our recent findings, we hypothesize that NCT and Aph-1 are required to regulate the stability of each other to form a stable pre-complex for assembly of PS and Pen-2. Since our recent studies indicated that PS1-/-;NCT+/- embryos exhibited a more severe phenotype as compared to PS1-/-;NCT+/- embryos, we hypothesize that this is due to reduced level of PS2-depenedant gamma-secretase complex in PST-/-;NCT+/- embryos. In Aim 2 we will to test whether PS2-dependent gamma-secretase activity is sensitive to the dosage of NCT in the absence of PS1. In addition, we plan to test whether partial reduction of both NCT and PS1 can further reduce the level of Abeta without altering Notch signaling. Positive outcomes from these studies provide support for the view that a combination of NCT- and PS-specific inhibitors may be a useful therapeutic strategy. In Aim 3, we will examine the impact of the absence of NCT in adult peripheral tissues by generation of transgenic mice expressing NCT under the control of the neuronal-specific Thy1 promoter to genetically complement the embryonic lethality of NCT-/- mice. Results from these studies will have important implications for understanding the biology of NCT and development of anti-Abeta therapeutic strategies in AD.